Insulin acts on fat and muscle to stimulate the translocation of Glut4 from an intracellular storage compartment to the plasma membrane, where it can remove excess glucose from the blood. The amount of Glut4 expressed in adipose tissue affects glucose tolerance and insulin sensitivity. Thus it is critical that we understand the molecular mechanisms regulating Glut4 expression in adipose tissue. We designed a screen to identify novel regulators of glucose uptake using short-interfering RNA (siRNA)-mediated gene silencing in 3T3-L1 adipocytes. Depletion of the transcriptional corepressor receptor interacting protein 140 (RIP140) enhanced glucose uptake, largely by increasing Glut4 expression. We thus hypothesize that RIP140 acts as a corepressor of Glut4 transcription. The increase in glucose uptake with RIP140 depletion required the presence of the transcription factor C/EBPa, but not the transcription factors PPARg or LXRa. We therefore hypothesize that RIP140 represses Glut4 expression through an interaction with C/EBPa. We propose to test these hypotheses in order to gain an understanding of the role of RIP140 in regulating Glut4 expression in adipocytes. [unreadable] [unreadable]